Metabolic responsive factors in cardiovascular disease

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PPAR^/, a major target for the antidiabetic thiazolidinediones (TZDs), is a transcription factor that occupies a position integrating metabolic and cardiovascular responses. PPAR-y is critical for adipogenesis and mutations in PPAR-y have been shown to cause insulin resistance, diabetes and hypertension. TZDs have recently been shown to alter blood pressure in animals and humans and to modify vascular endothelial and smooth muscle function. Therefore, PPAR-y is likely candidate for mediating the interface between metabolic disease and cardiovascular disease. However, it is unclear if PPAR-y in vascular tissues is critical to in vivo responses and whether TZD effects on vascular function are mediated by PPAR-y. Our goal is to determine the role of PPAR--y in cardiac and vascular cells and to determine its role in mediating the associations of metabolic and cardiovascular diseases. This proposal will answer three critical questions. What is the physiologic function of PPAR-y in the cardiovascular system in otherwise normal animals? What is the role of PPAR-y in pathologic disease models? Finally, what are the mechanisms of PPAR-y and TZD effects (i.e. what TZD effects mediated by PPAR-y and what are the molecular mechanisms?)? To answer these questions, we have produced a novel "whole body" PPAR-y knockout, cardiomyocyte and endothelial cell-type restricted knockouts and propose smooth muscle cell knockouts. We will use a multidisciplinary approach, focused on these gene knockouts, to determine the physiologic role and mechanisms of action of the cardiovascular PPAR-y. By determining the phenotype of these knockout animals we anticipate defining the role of PPAR-y in cardiovascular tissue. Therefore, we will be able to determine if PPAR-y mediates TZD effects. Based on our preliminary data, we will test the hypothesis that PPAR-y is critical to normal regulation of cardiovascular cell growth, protects cells from diabetic glucolipotoxicity and regulates blood pressure (likely predominately in the endothelial cell)-All in a physiologic important context..